Nishimura Toshihide, Nakamura Haruhiko
Translational Medicine Informatics, St. Mariana University School of Medicine, Kanagawa, Japan.
Research & Development, Biosys Technologies Inc., Tokyo, Japan.
Adv Exp Med Biol. 2016;926:115-137. doi: 10.1007/978-3-319-42316-6_8.
Molecular therapies targeting lung cancers with mutated epidermal growth factor receptor (EGFR) by EGFR-tyrosin kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, changed the treatment system of lung cancer. It was revealed that drug efficacy differs by race (e.g., Caucasians vs. Asians) due to oncogenic driver mutations specific to each race, exemplified by gefitinib / erlotinib. The molecular target drugs for lung cancer with anaplastic lymphoma kinase (ALK) gene translocation (the fusion gene, EML4-ALK) was approved, and those targeting lung cancers addicted ROS1, RET, and HER2 have been under development. Both identification and quantification of gatekeeper mutations need to be performed using lung cancer tissue specimens obtained from patients to improve the treatment for lung cancer patients: (1) identification and quantitation data of targeted mutated proteins, including investigation of mutation heterogeneity within a tissue; (2) exploratory mass spectrometry (MS)-based clinical proteogenomic analysis of mutated proteins; and also importantly (3) analysis of dynamic protein-protein interaction (PPI) networks of proteins significantly related to a subgroup of patients with lung cancer not only with good efficacy but also with acquired resistance. MS-based proteogenomics is a promising approach to directly capture mutated and fusion proteins expressed in a clinical sample. Technological developments are further expected, which will provide a powerful solution for the stratification of patients and drug discovery (Precision Medicine).
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（EGFR-TKIs）吉非替尼和厄洛替尼靶向治疗具有EGFR突变的肺癌，改变了肺癌的治疗体系。研究表明，由于各人群特异性的致癌驱动突变，药物疗效存在种族差异（如白种人与亚洲人），吉非替尼/厄洛替尼就是例证。针对具有间变性淋巴瘤激酶（ALK）基因易位（融合基因EML4-ALK）的肺癌的分子靶向药物已获批，针对对ROS1、RET和HER2成瘾的肺癌的药物也在研发中。为改善肺癌患者的治疗，需要使用从患者获取的肺癌组织标本进行守门人突变的鉴定和定量：（1）靶向突变蛋白的鉴定和定量数据，包括组织内突变异质性的研究；（2）基于探索性质谱（MS）的突变蛋白临床蛋白质基因组分析；同样重要的是（3）对不仅疗效良好而且具有获得性耐药的肺癌患者亚组中与蛋白质显著相关的动态蛋白质-蛋白质相互作用（PPI）网络的分析。基于MS的蛋白质基因组学是直接捕获临床样本中表达的突变和融合蛋白的一种有前景的方法。预计技术将进一步发展，这将为患者分层和药物发现（精准医学）提供强有力的解决方案。
